Cassandra Wilson is the third and youngest child of Herman Fowlkes, Jr., a guitarist, bassist, and music teacher;[3] and Mary McDaniel, an elementary school teacher who earned her PhD in education. Her ancestry includes Fon, Yoruba, Irish and Welsh. Between her mother’s love for Motown and her father’s dedication to jazz, Wilson’s parents sparked her early interest in music.[4]

Wilson’s earliest formal musical education consisted of classical lessons; she studied piano from the age of six to thirteen and played clarinet in the middle school concert and marching bands.[4] When she was tired of this training, she asked her father to teach her the guitar. Instead, he gave her a lesson in self-reliance, suggesting she study Mel Bay method books. Wilson explored guitar on her own, developing what she has described as an “intuitive” approach. During this time she began writing her own songs, adopting a folk style. She also appeared in the musical theater productions, including The Wizard of Oz as Dorothy, crossing racial lines in a recently desegregated school system.

In 1981, she moved to New Orleans for a position as assistant public affairs director for the local television station, WDSU. She did not stay long. Working with mentors who included elder statesmen Earl Turbinton, Alvin Batiste, and Ellis Marsalis, Wilson found encouragement to seriously pursue jazz performance and moved to New York City the following year.

The M-Base group in Brooklyn, working with both jazz and pop forms, makes music that at first sounds like funk from the 1970s. Like the music played by Mr. Marsalis (and his brother Wynton) the music made by M-Base - Steve Coleman, with Greg Osby, Cassandra Wilson and Geri Allen – is, at its best, filled with subtle ideas working behind the mask of popular music. In Mr. Coleman's group a singer is supported by an electric bass, guitar, drums and electric keyboards, a shiny musical mix that has familiar rock and funk references; yet, because of all its rhythmic and metric manipulations, sounds new.[5]

Although the voice – typically treated as the focal point of any arrangement in which it is included – was not an obvious choice for M-Base's complex textures or harmonically elaborated melodies, Wilson wove herself into the fabric of these settings with wordless improv and lyrics. She can be heard on Coleman's debut as a leader Motherland Pulse (1985), then as member of his Five Elements on On the Edge of Tomorrow (1986), World Expansion (1986), Sine Die (1987), and on M-Base Collective's sole recording as a large ensemble Anatomy of a Groove (1992).

At the same time, Wilson toured with avant-garde trio New Air featuring alto saxophonist Henry Threadgill and recorded Air Show No. 1 (1987) in Italy. A decade her senior and an AACM member, Threadgill has been lauded as a composer for his ability to transcend stylistic boundaries, a trait he and Wilson share.

Like fellow M-Base artists, Wilson signed to the Munich-based, independent label JMT. She released her first recording as a leader Point of View in 1986. Like the majority of her JMT albums that followed, originals by Wilson in keeping with M-Base dominated these sessions; she would also record material by and co-written with Coleman, Jean-Paul Bourelly, and James Weidman as well as a few standards. Her throaty contralto gradually emerges over the course of these recordings, making its way to the foreground. She developed a remarkable ability to stretch and bend pitches, elongate syllables, manipulate tone and timbre from dusky to hollow.[6]

While these recordings established her as a serious musician, Wilson received her first broad critical acclaim for the album of standards recorded in the middle of this period, Blue Skies (1988). Her signing with Blue Note Records in 1993 marked a crucial turning point in her career and major breakthrough to audiences beyond jazz with albums selling in the hundreds of thousands of copies.

Not only did Wilson effectively reconnect vocal jazz with its blues roots, she was arguably the first to convincingly fashion post–British Invasion pop into jazz, trailblazing a path that many have since followed. Furthermore, producer Craig Street drew from pop production techniques to create a rich ambient environment around her voice, magnifying it and giving sonic depth to Brandon Ross' sparse but incredibly vivid arrangements, which used steel guitar, violin, accordion, and percussion.

The late Miles Davis was one of Wilson's greatest influences. In 1989, Wilson performed as the opening act for Davis at the JVC Jazz Festival in Chicago. In 1999 she produced Traveling Miles as a tribute to Davis. The album developed from a series of jazz concerts that she performed at Lincoln Center in November 1997 in Davis' honor, and includes three selections based on Davis' own compositions, from which Wilson adapted the original themes.

She has a son, Jeris, born in the late 1980s. Her song "Out Loud (Jeris' Blues)" on the album She Who Weeps is dedicated to him. For many years she and her son lived in New York City's Sugar Hill, in an apartment that once belonged to Count Basie, Lena Horne and the boxer Joe Louis.[8]

In 2000, Wilson married actor Isaach de Bankolé, who directed her in the concert film Traveling Miles: Cassandra Wilson (2000).